Inactivation of the Hippo tumor suppressor pathway promotes melanoma

Abstract

Melanoma is commonly driven by activating mutations in the MAP kinase BRAF; however, oncogenic BRAF alone is insufficient to promote melanomagenesis. Instead, its expression induces a transient proliferative burst that ultimately ceases with the development of benign nevi comprised of growth-arrested melanocytes. The tumor suppressive mechanisms that restrain nevus melanocyte proliferation remain poorly understood. Here we utilize cell and murine models to demonstrate that oncogenic BRAF leads to activation of the Hippo tumor suppressor pathway, both in melanocytes in vitro and nevus melanocytes in vivo. Mechanistically, we show that oncogenic BRAF promotes both ERK-dependent alterations in the actin cytoskeleton and whole-genome doubling events, which independently reduce RhoA activity to promote Hippo activation. We also demonstrate that functional impairment of the Hippo pathway enables oncogenic BRAF-expressing melanocytes to bypass nevus formation and rapidly form melanomas. Our data reveal that the Hippo pathway enforces the stable arrest of nevus melanocytes and represents a critical barrier to melanoma development.

The role of yes activated protein (YAP) in melanoma metastasis

“… 59 Similarly, expression of constitutively active YAP in zebrafish potently induces melanogenesis. 66 …”

Whole-Genome Doubling as a source of cancer: how, when, where, and why?

“…Furthermore, both pathways, p53, and HIPPO, are interconnected via LATS2 (a HIPPO effector) ensuring the G1 arrest after WGD ( Aylon et al, 2006 ). Even the presence of oncogenic alterations such as B-RAFV600E display WGD ( Darp et al, 2022 ) and activates p53 and HIPPO pathways thus preventing proliferation ( Vittoria et al, 2022 ). In fact, p53, LATS2, and the PIDDdosome have been proposed to form part of a “tetraploid checkpoint” that prevents tetraploid cells from re-entering the cell cycle, since the inactivation of either gene reverses the G1 arrest ( Aylon et al, 2006 ; Aylon and Oren, 2011 ; Ganem et al, 2014 ; Sladky et al, 2020b ).…”

“…Interestingly, oncogenic B-RAFV600E also induces HIPPO pathway activation and cell cycle arrest in vitro as well as in nevus melanocytes in vivo . Deletion of HIPPO regulators, such as LATS1/2 in this oncogenic background, has a strong tumorigenic potential permitting oncogenic B-RAF expressing melanocytes to bypass nevus formation ( Vittoria et al, 2022 ). Similarly, the oncogene v-Src is a negative modulator of the HIPPO pathway, by LATS1/2 inactivation, leading to YAP activation and the generation of tetraploid cells ( Kakae et al, 2017 ).…”

Organoids: approaches and utility in cancer research

“…Recently, genetically engineered mouse tumor models have been established using gene editing. Tumorigenesis can be caused by activation of proto-oncogenes, overexpression of oncogenes, [41] or knockout of tumor suppressor genes [42] . In addition, modification of immune system-related or stromal-related genes can drive or promote tumorigenesis [43] …”

“…Tumorigenesis can be caused by activation of proto-oncogenes, overexpression of oncogenes, [41] or knockout of tumor suppressor genes. [42] In addition, modification of immune system-related or stromal-related genes can drive or promote tumorigenesis. [43] Tumor xenograft models culture conditions in vitro to form stable tumor cell lines, which were then injected into immunodeficient mice.…”